The present invention relates to novel compounds which inhibit protein kinase C (hereafter referred to as C-kinase) and have activities such as anti-tumor activity.
C-kinase is a protein kinase which is activated depending upon phospholipids and calcium and widely distributed over tissues and organs in the living body. In recent years, it has become known that this enzyme plays an extremely important role in cell membrane receptor transduction mechanism in which many hormones, neurotransmitters, etc. are concerned. As examples of physiological response induced by the signal transduction system in which C-kinase participates, there have been reported serotonine release from platelets, lysosomal enzyme release and aggregation, superoxide formation and lysosomal enzyme release from neutrophil leukocytes, epinephrine release from adrenal medulla, secretion of aldosterone from renal glomerulus, secretion of insulin from Langerhans' islet, histamine release from mast cells, acetylcholine release from ileum, contraction of vascular smooth muscle, and the like. C-kinase is also supposed to be concerned in cell growth and carcinogenetic mechanism [Y. Nishizuka, Science, 225, 1365 (1984); H. Rasmussen et al., Advance in Cyclic Nucleotide and Protein Phosphorylation Research, vol. 18, p. 159, edited by P. Greengard and G. A. Robinson, Raven Press, New York, 1984]. It has thus been clarified that C-kinase takes part in many important physiological responses in vivo and various morbid conditions. Therefore, it is expected that a wide variety of diseases such as diseases of the circular system, inflammatory diseases, allergy and tumor can be prevented or treated by artificially inhibiting C-kinase activity by the use of specific inhibitors, etc.
On the other hand, it has been found that antipsychotic drugs such as trifluoperazine and chlorpromazine, dibenamine and tetracaine which are known as local anesthetics, calmodulin inhibitor W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], etc. possess C-kinase inhibitory activity. However, the C-kinase inhibitory activity is not the main activity of these drugs, and they only exhibit low inhibitory activity against C-kinase with low specificity [Y. Nishizuka et al., J. Biol. Chem., 255, 8378 (1980); R. C. Schatzman et al., Biochem. Biophys. Res. Commun., 98, 669 (1981); B. C. Wise et al., J. Biol. Chem., 257, 8489 (1982)].
Further, K-252 and KT-5556 represented by the following formula (II) and K-252 derivatives in which R.sub.A and R.sub.B are modified are known (with K-252, see Japanese Published Unexamined Patent Application No. 41489/85 and U.S. Pat. No. 4,555,402; with KT-5556, see Japanese Published Unexamined Patent Application No. 176531/86; and with the K-252 derivatives, see Japanese Published Unexamined Patent Application Nos. 155284/87 and 155285/87). ##STR2##
In Japanese Published Unexamined Patent Application No. 41489/85, it is described that K-252 has activity to inhibit histamine release and anti-allergic activity, and in Japanese Published Unexamined Patent Application Nos. 155284/87 and 155285/87, it is described that the K-252 derivatives have C-kinase inhibitory activity and antivity to inhibit histamine release. It is described in Japanese Published Unexamined Patent Application No. 176531/86 that KT-5556 has activity to inhibit histamine release. In addition, compounds that are assumed to be identical with K-252 or KT-5556 have been reported as antibacterial substances [M. Senzaki et al., J. Antibiotics, 38, 1437 (1985)]. In this publication, a compound of the above formula wherein R.sub.A =CO.sub.2 CH.sub.3 and R.sub.B =COCH.sub.3 is also disclosed. The compound assumed to be identical with K-252 and its halogen derivatives are disclosed in Japanese Published Unexamined Patent Application Nos. 120388/87 and 164626/87 and derivatives wherein R.sub.A is modified are disclosed in Japanese Published Unexamined Patent Application No. 240689/87, all as the compounds possessing hypotensive action and diuretic action.
Furthermore, Staurosporine having the following structure and antibacterial activity is known as a compound having a structure relatively akin to that of K-252 [S. Omura et al., J. Antibiotics, 30, 275 (1977); A. Furusaki et al., J. Chem. Soc. Chem. Commun., 800 (1978); Japanese Published Unexamined Patent Application No. 185719/85]. ##STR3##
A novel active ingredient for an anti-tumor agent, etc. which has a high C-kinase inhibitory activity is always in demand.